The, immune system is regulated by specific cell-cell interactions that are mediated through an elaborate array of cell-surface receptors. While the identity of many of the cell-surface receptors is known, the mechanisms by which they exert their influence on immune responses remains obscure in most instances. This is especially true in autoimmune diseases, where the failure to regulate immune responses properly results in a pathological state. Among the cell surface receptors implicated in normal, as well as inflammatory, responses, is CD69. CD69 is expressed on the surface of activated, but not resting, cells of all hematopoietic lineages. It has been shown to be involved in a wide variety of biological processes, including the positive selection of thymocytes, induction of proinflammatory cytokine release from monocytes, and T cell co- stimulation. In spite of the overwhelming evidence demonstrating the importance of CD69 to the development and function of the immune system, there is very little known as to how CD69 is regulated or how it functions. Very basic issues, such as the mechanism of CD69 signal transduction and the nature of its cognate ligand, as well as more global issues such as its role in mounting a competent immune response and propagating a chronic pathological state, remain unanswered. A wide body of evidence suggests that CD69 plays an important role in two aspects of the immune system, thymocyte development and T cell activation, that are also areas of immune dysfunction in autoimmune disease. However, before an assessment of CD69's role in autoimmune disease can be made, a detailed analysis of its role in the normal development and function of the immune system must be performed. The experiments described in this proposal will address basic questions concerning the role of CD69 in the positive selection of thymocytes, as well as the mechanism by which CD69 transmits intracellular signals. We will also identify and characterize the cell surface molecule on monocytes that serves as the CD69 receptor. Knowing this information will allow a detailed analysis of the role of CD69 in the initiation and propagation of autoimmune disease to be initiated.